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drugINTERACTIONS: insights and observations
Understanding an Important
Variable in Patient Response
John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD
Table
Drs. Horn and Hansten are both professors of pharmacy at the University
of Washington School of Pharmacy.
For an electronic version of this article, visit www.hanstenandhorn.com.
t is known that differences in the
genetic makeup of drug-metabolizing
enzymes (genotypes) can influence
the outcome of drug therapy. These
genetic differences are also responsible
for some of the variability we see in
patient responses to drug–drug interactions. The Table lists 3 common drugmetabolizing enzymes that are known to
have different genotypes. When patients
have normal genes coding for an enzyme,
they are known as extensive metabolizers (EMs). If one or more genes for the
enzyme are abnormal (mutant), this may
reduce the activity of the enzyme and
slow the metabolism of drugs that are
substrates for the enzyme. Patients with
abnormal genes that result in malfunctioning enzymes are referred to as poor
metabolizers (PMs). Drug interactions
caused by enzyme inhibitors cause a similar reduction in the metabolism of substrates for the inhibited enzyme.
Usually when a drug is administered, it
is converted to inactive metabolites by
enzymes. If the patient is a PM, the drug’s
clearance is reduced, and the drug will
accumulate in the body, perhaps resulting in toxicity. Metoprolol is metabolized
primarily by the enzyme cytochrome
P-450 2D6 (CYP2D6). The clearance of
metoprolol in EMs is about 5 to 6 times
greater than in PMs. Thus, PMs of metoprolol are more likely to develop an
adverse drug reaction (ADR). When a
drug that inhibits CYP2D6 (eg, diphenhydramine [Benadryl]) is administered to an
EM who is receiving metoprolol, the
rapid metabolism of metoprolol will be
markedly reduced. The resulting eleva-
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n
Genotypes of Drug-metabolizing Enzymes
Enzyme
CYP2C9
Frequency of PMs
6%-8% Caucasians
CYP2C19
3%-5% Caucasians
12%-23% Asians
6%-10% Caucasians
2%-5% African Americans
1% Asians
CYP2D6
Examples of Substrates
Tolbutamide, glyburide,
glipizide, warfarin
Diazepam, omeprazole,
pantoprazole
Codeine, imipramine,
metoprolol, timolol
PMs = poor metabolizers.
tion of metoprolol plasma concentrations may potentially result in an ADR. If
a patient receiving metoprolol is deficient
in the CYP2D6 enzyme, the coadministration of diphenhydramine will have
very little effect.1 This is because the PM
patient has little or no CYP2D6 enzyme
that can be inhibited by the diphenhydramine. Thus, the PM patient is actually
less likely to experience an ADR from a
drug interaction with a CYP2D6 inhibitor
than an EM patient.
Codeine is a prodrug that is converted
in vivo to the analgesic morphine by
CYP2D6. Patients who are CYP2D6 PMs
will not convert codeine to morphine and
will have a reduced analgesic effect from
codeine. When patients who are CYP2D6
EMs are administered a CYP2D6 inhibitor, they do not convert much codeine to
morphine and have a minimal analgesic
response to the codeine.2 In the case of
codeine, administering a CYP2D6 inhibitor produces a similar outcome, as
does the absence of the CYP2D6 enzyme. In both cases, a loss of analgesic
effect is likely. Giving a patient who is a
CYP2D6 PM a drug that is an inhibitor of
CYP2D6 will not add to the reduced
codeine metabolism produced by the
genetic deficiency.
About 50% of lansoprazole’s metabolism is via the CYP2C19 enzyme. PMs for
CYP2C19 have plasma lansoprazole concentrations that are about 4 to 5 times
September 2006 | Pharmacy Times
higher than EMs.3 When lansoprazole
was administered with tacrolimus, the
mean tacrolimus concentrations increased >80% in the participants who
were CYP2C19 PMs and <30% in the
EMs.4 Tacrolimus is not considered to be
a substrate for CYP2C19. The higher plasma concentrations of lansoprazole found
in the PMs resulted in a greater magnitude interaction with tacrolimus than in
the EMs who had much lower lansoprazole plasma concentrations. While the
mechanism of this interaction is not certain, the lack of CYP2C19 metabolism
increased the concentration of the precipitant drug (lansoprazole) and
increased the magnitude of its effect on
the object drug (tacrolimus).
Changes in drug–drug interaction outcomes can be influenced by a patient’s
genetics. Being genetically deficient in an
enzyme may either protect the patient
from an interaction or increase the magnitude of one. The influence of genetics
on drug–drug interactions needs to be
considered for any interaction that
involves enzymes that are known to
have variable expression based on a
patient’s genetic composition. PT
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